Various scientific articles and patent publications are referenced herein to describe the state of the art to which this invention pertains. Each of these publications is incorporated by reference herein in its entirety.
Hormone therapy using synthetic estrogens and/or progestins is currently used to control fertility and for treatment or prevention of a variety of hormone-related conditions or deficiencies, including control of acne, treatment of endometriosis, induction or prevention of amenorrhea, supporting pregnancy and treatment of galactorrhea, among numerous others. Traditionally, combinations of synthetic estrogen and synthetic progestin have been used in the past in orally administered dosage forms. Though the combination of synthetic progestin and estrogen effectively suppresses ovulation, certain undesirable side effects are associated with this type of oral contraceptive. For instance, the incidence of thromboembolic and related vascular disorders, including stroke and myocardial infarction, is higher in women using oral contraceptives; the relative risk may be eleven times greater in users as compared to a control population. Further, the risk increases sharply in women over 35 years of age. Contraceptive use has also been associated with increased evidence of benign liver tumors and an increased risk of gallbladder disease. Additionally, fetal abnormalities may result if a woman continues to take the pill after becoming pregnant.
Transdermal hormone delivery offers many advantages and avoids certain disadvantages associated with oral contraceptives and hormone treatments. Specifically, transdermal rate-controlled drug administration avoids the variability in absorption and metabolism associated with oral therapy. It further provides continuity of drug administration, permitting the use of a pharmacologically active agent with short biological half-life. Moreover, there is less chance of over- or under-dosing on a transdermal regimen, and patient compliance with a multi-day easy-to-use transdermal regimen is superior to daily oral dosing.
It is, therefore, highly desirable to provide formulations and transdermal systems that permit 1) use of high levels of progestin, 2) use of either synthetic or natural estrogen, 3) use of a minimum number of dosage units for each menstrual cycle, and further that provide appropriate levels of progestin and estrogen hormones to fully ensure fertility control or other treatment goals with minimal or no production of undesired metabolic or chemical degradative products.
In recent years various transdermal contraceptive delivery systems for fertility control in females have been developed. U.S. Pat. No. 5,296,230 describes a transdermal fertility controlling polymer matrix dosage unit comprising a backing layer, a polymer layer adhered to the backing layer comprising microdispersed dosage amounts of estrogen and progestin hormones, and an adhesive layer. U.S. Pat. No. 5,560,922 discloses the delivery of a natural estrogen, 17β-estradiol, or ethinyl estradiol or a combination thereof with an amount of natural progesterone or a progestin in a dosage unit comprising a backing layer and an adjoining polyacrylate adhesive polymer layer containing microreservoirs that release the hormones.
U.S. Pat. No. 5,788,983 discloses a transdermal polymer dosage unit, a backing layer and a reservoir layer, the reservoir layer having multiple regions that contact the skin during use and optionally contain difference pharmaceutical therapeutic agents providing a variable rate of absorption. U.S. Pat. No. 5,762,956 describes a transdermal contraceptive delivery device and a method of fertility control utilizing the device. The system comprises a backing layer, and an adhesive polymer matrix, which has dispersed therein hormones effective for controlling fertility, as well as a combination of three skin permeation enhancers at a specified relative weight ratio.
The above described transdermal delivery systems are deficient in their ability to deliver sufficient quantities of progestin, particularly levonorgestrel, either alone or in proper balance with a selected estrogen, for one or more of a variety of reasons. For instance, the systems described in U.S. Pat. Nos. 5,296,230, 5,560,922 and 5,788,983 comprise dosage units that are cumbersome in size, e.g., with surface area up to 100 cm2. The dosage unit described in U.S. Pat. No. 5,762,956 is purportedly smaller, but the amount of progestin delivered is not robust.
Accordingly, there is a need in the art for a transdermal hormone delivery system, and drug-delivery formulations for use therein, that can reliably achieve high serum levels of hard-to-deliver progestins, such as levonorgestrel, and a desired profile of progestin and selected estrogen for contraception and other purposes, with minimal side effects. It is also desirable that the dosage unit is comfortably-sized, cosmetically unobtrusive and reliably adherent.